Members in the News

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Kathleen M. Carroll, PhD was appointed to the Substance Use Disorders Coordinating Committee (ISUDCC) by the Alex Azar, HHS Secretary. October 16, 2019Dr. Ryan T. Lacy: Using Preclinical Models to Evaluate the Influence of Biological Sex and Gonadal Hormones on Substance Use

By Justin C. Strickland, Ph.D., Animals in Research Committee Member

The influence of biological sex and gonadal hormones on substance use remains an important area of research in addiction science. Epidemiological data highlight the role that biological sex may play in the development of substance use disorders as well as a resistance to intervention. Animal models help provide important information about the role of these sex differences in drug-taking behavior by isolating the influence of biological sex across varied stages of substance use disorder.

New research by Dr. Ryan Lacy at Franklin & Marshall College uses a preclinical model of behavioral economic demand to evaluate the role of biological sex and gonadal hormones on opioid and cocaine use. This study is a part of Dr. Lacy’s broader research program utilizing preclinical models to evaluate the neurobiological and behavioral effects of gonadal sex hormones on drug-seeking and drug-taking behavior.

Male and female rats were tested using a within-session threshold procedure to determine behavioral economic demand for cocaine and the short-acting opioid remifentanil. This threshold procedure allows for the rapid evaluation of drug demand by manipulating the “cost” of a substance within a single session. Responses can be modeled using behavioral economic demand functions to determine independent behavioral mechanisms underlying consumption, including use at unconstrained price and price sensitivity. This procedure provides a translationally relevant measure of substance use by evaluating the consumption of a drug under competing environmental costs in a way that can be similarly evaluated in the human laboratory and clinic. Subjects were tested for cocaine and remifentanil demand using this threshold procedure over 15 days in a counterbalanced testing order.

Overall, no differences between male and female subjects were observed for cocaine or remifentanil demand. However, among female subjects, a significant effect of freely cycling hormones was observed. Female subjects showed higher levels of unconstrained demand (consumption at low cost) for both cocaine and remifentanil during times in which circulating estrogen was high (i.e., during the estrus phase). These effects were detected by tracking and recording estrous cyclicity throughout behavioral testing using a vaginal lavage procedure. This low-cost and relatively noninvasive procedure is one that any laboratory conducting research with female subjects can effectively and efficiently incorporate into their studies to evaluate gonadal hormones without the need for additional surgical procedures and/or exogenous hormone administration.

The counterbalanced testing order of remifentanil and cocaine afforded the opportunity to study exposure effects on drug demand. These analyses indicated a robust effect of prior remifentanil exposure on cocaine demand with increases in cocaine intake at low price and diminished price sensitivity. Exposure effects were pharmacologically specific in that prior cocaine exposure did not impact remifentanil demand. Sex differences were not observed for these exposure effects, consistent with the lack of sex differences in overall drug demand.

This study highlights the importance of including male and female subjects in behavioral pharmacology research as well as the utility of using preclinical animal models for evaluating the influence (or lack of influence) of biological sex and gonadal hormones on substance use. Preclinical research historically used only male subjects due to concerns over cycling sex hormones in female subjects. Recently, however, researchers such as Dr. Lacy have seen the inclusion of female subjects not as a limitation, but as an opportunity to improve the generalizability and richness of preclinical research. This body of preclinical work represents an important foundation for understanding the neurobiology of sex differences in drug-taking behaviors to help ensure the effective and comprehensive development of prevention and treatment efforts for substance use disorder.

Ryan Lacy has been a member of CPDD since 2008 and currently serves on the Publications committee. Justin Strickland has been a member of CPDD since 2014 and currently serves on the Animals in Research and Travel Award committees.

The study was supported by Research Development Funds from Franklin & Marshall College and the National Science Foundation. This study is published in Addiction Biology.